- Email: [email protected]
Synthesis of two possible diastereomers of reticulatain-1
Tetrahedron Letters Tetrahedron Letters 45 (2004) 973–977
Synthesis of two possible diastereomers of reticulatain-1 Hidefumi Makabe,a,* Aya Miyawaki,a Ryoko Takahashi,a Yasunao Hattori,a Hiroyuki Konno,b Masato Abec and Hideto Miyoshic a
Sciences of Functional Foods, Graduate School of Agriculture, Shinshu University, 8304 Minami-minowa, Kamiina, Nagano 399-4598, Japan b Department of Biological Science and Technology, Faculty of Engineering University of Tokushima, 2-1 Minamijosanjimacho, Tokushima 770-8506, Japan c Division of Applied Sciences, Graduate School of Agriculture, Kyoto University, Kita-shirakawa, Sakyo-ku, Kyoto 606-8502, Japan Received 25 September 2003; revised 20 November 2003; accepted 21 November 2003
Abstract—A convergent synthesis of two possible diastereomers of reticulatain-1 (1a and 1b) was accomplished. Comparison of the specific optical rotations of 1a and 1b did not allow for the strict determination of the absolute configuration. However, bis-(R)MTPA esters of 1a and 1b showed a clear difference in chemical shifts in the 1 H NMR spectra. If the bis-(R)-MTPA ester of natural reticulatain-1 (1) is available, the absolute configuration of 1 will be determined. Inhibitory action of these compounds was examined with bovine heart mitochondrial complex I. Both compounds showed almost the same activity. Ó 2003 Elsevier Ltd. All rights reserved.
Annonaceous acetogenins, that have been isolated from a number of tropical or subtropical plants of the Annonaceae, have attracted much attention due to a wide variety of biological activities, for example, cytotoxic, antitumoral, antimalarial, antibiotic, antiparasitic, and antifeedant. So far, more than 350 compounds have been isolated.1 Most of them possess one or more tetrahydrofuran (THF) rings, together with an a,b-unsaturated c-lactone part on a C-35 or C-37 carbon chain. Reticulatain-1 (1) is a mono-THF acetogenin,2 isolated from Annona reticulata in 1995.3 A similar compound corresponding to the well-known reticulatacin (2)4 was synthesized by Keinan5 and us.6 The absolute configuration of natural 1 has not been reported yet. However, because the erythro-trans-threo stereochemistry of the tetrahydrofuran ring of 1 has been determined by Figadere et al.,3 and the (S) configuration of the secondary methyl group of the c-lactone moiety is well known, it follows that the absolute stereochemistry of 1 is (17R,18R,21R,22S) or (17S,18S,21S,22R) (Fig. 1).
trans erythro C12H25
O
threo
O
O
OH
OH 21
18
O
22
reticulatain-1 (1)
OH
21 17
OH
18
O
22
OH
1a
17
OH 1b O
C12H25
O
O OH
OH
reticulatacin (2)
trans threo C12H25 OH
threo
OH
O O
O OH
(8'R)-corossoline (3)
Figure 1. The structure of reticulatain-1.
The two possible structures, 1a and 1b, would be very difficult to differentiate by 1 H NMR or 13 C NMR
Keywords: Annonaceous acetogenin; Antitumor; Mitochondrial complex I. * Corresponding author. Tel.: +81-265-77-1630; fax: +81-265-77-1700; e-mail: [email protected] 0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2003.11.109
spectroscopic data, because two stereogenic centers, that is, the THF ring part and the c-lactone moiety are separated by a long carbon chain. In a previous paper, we prepared chiral building block 4 for synthesizing (80 R)-corossoline (3), mono-THF acetogenins, which possess the threo-trans-threo stereochemistry of the
974
H. Makabe et al. / Tetrahedron Letters 45 (2004) 973–977 Ref. 7 +
CHO
C12H25
C12H25MgBr
OH
O
Ref. 7
Ref. 7 C12H25 C12H25
O
O OH
AD mix β
3 O OMOM 5
OMOM
O C12H25
4 Mitsunobu Inversion and Hydrolysis
C12H25
O
O OH
O 6
O OMOM 7a
OMOM
I
C12H25
O OMOM OMOM 7a trans erythro threo C12H25 O OH OH 1a
+
O
O
8 O O
Scheme 1. Synthetic strategy of reticulatain-1.
tetrahydrofuran ring. In this paper, we prepared another chiral building block 6 for synthesizing mono-THF acetogenins, which possess erythro-trans-threo stereochemistry by using the Mitsunobu inversion from 4 (Scheme 1). To utilize this methodology, we planned to synthesize two candidates of reticulatain-1 (1), 1a and 1b.
acrolein and laurylmagnesium bromide. Grignard reaction of acrolein with laurylmagnesium bromide gave allylic alcohol 9. Johnson–Claisen rearrangement with 1,1,1-triethoxyethane and a catalytic amount of propionic acid gave ester 10, which was then submitted to reduction with diisobutylaluminum hydride (DIBALH) to afford 11. The conversion of compound 11 to 4 was performed using the Sharpless epoxidation and dihydroxylation according to our previously published method.7
As shown in Scheme 2, the THF part 15 of 1a was constructed via a multi-step process starting from OH
a
CHO acrolein
C12H25
d
C12H25
OH
OH
O 6
C12H25
C12H25
O OMOM 14
h
OH OH
j O OMOM 16
C12H25
O
C12H25
O OMOM 15
O OMOM 13
OH
O
O
g
O
OTBS
i
OH
k O OMOM 17
O O-p-NBA O 12
O C12H25
f
O
O
4
C12H25
O
O OH
C12H25
c
10
9
11 e
CO2Et
C12H25
Ref. 7 C12H25
b
C12H25
O OMOM OMOM 7a
Scheme 2. Synthesis of tetrahydrofuran part of 1a. Reagents: (a) C12 H25 MgBr, Et2 O (95%); (b) CH3 C(OEt)3 , propionic acid (86%); (c) DIBALH, CH2 Cl2 (95%); (d) p-nitrobenzoic acid, DEAD, THF (85%); (e) NaOH, MeOH (91%); (f) MOMCl, i-Pr2 NEt, CH2 Cl2 (92%); (g) 60% AcOH, (96%); (h) TBSCl, Et3 N, DMAP, CH2 Cl2 (100%); (i) 1) MsCl, Et3 N, CH2 Cl2 2) TBAF, THF(96%); (j) lithium acetylide, ethylenediamine complex, DMSO (83%); (k) MOMCl, i-Pr2 NEt, CH2 Cl2 (94%).
H. Makabe et al. / Tetrahedron Letters 45 (2004) 973–977
The spectral data (1 H NMR, 13 C NMR, EIMS) of the synthetic 1a and 1b were in good agreement with those reported for natural 1.3 This indicates that the relative stereochemistry of natural 1 is erythro-trans-threo as reported by Figadere et al.3 The two synthetic samples (1a, 1b) could not be differentiated by the spectral data (1 H NMR, 13 C NMR, MS). On the other hand, their optical rotations showed different values. The specific rotation of synthetic 1a (½a30 D +9.68°, c 1.00, CHCl3 ) is lower than the reported value of natural occurring reticulatain )13 (½aD +22°, c 1, CHCl3 ). On the other 27 hand, that of 1b (½aD +2.34°, c 1.00, CHCl3 ) showed 13 a very small value. Judging from the specific optical rotations of 1a and 1b, it is difficult to determine the absolute configuration of natural reticulatain-1.2e;14 We also prepared the corresponding bis-(R)-MTPA esters from synthetic 1a and 1b. The chemical shifts of H-17, H-18, H-21, and H-22 of both 1a and 1b showed a clear difference and they were in good agreement with those of the methine protons of Fujimotos stereochemically defined model compounds (Fig. 2, Table 2).15
Table 1. Variation of the carboxylic acids in the Mitsunobu inversion of 4a
a
Acid
pKa
Yield (%)
Acetic acid Benzoic acid p-Nitrobenzoic acid
4.76 4.19 3.41
0 17 85
The reaction was carried out in THF at room temperature for 12 h.
Compound 4 was then subjected to the Mitsunobu reaction.8 In this reaction, the yields of products were highly dependent on the pKa values of acids perhaps due to the steric hindrance of the acetonide group.9 p-Nitrobezoate gave a good result. On the other hand, acetic acid or benzoic acid afforded the product in low yield (Table 1). Hydrolysis of p-nitrobezoate 12 with methanolic NaOH gave building block 6. The inverted secondary hydroxyl group of 12 was protected as the methoxymethyl (MOM) ether to afford 13. Selective deprotection of the acetonide group of 13 with 60% AcOH gave diol 14. Silylation of the primary hydroxyl group of 14 with t-butyldimethylchlorosilane (TBSCl), Et3 N, and 4-dimethylaminopyridine (DMAP) afforded 15. Successive treatment with methanesulfonyl chloride (MsCl), tetrabutylammonium fluoride (TBAF) furnished terminal epoxide 16. Alkynylation with lithium acetylide, an ethylene diamine complex, afforded alkyne 17. Protection of the secondary hydroxyl group gave the THF moiety 7a.
This indicates that if the bis-(R)-MTPA ester of natural 1 is available, the absolute configuration of reticulatain1 will be definitely established. Compounds 1a and 1b were tested as inhibitors of bovine-heart mitochondrial complex I. Both compounds exhibited almost the same activity (1a: IC50 ¼ 16 nM, 1b: IC50 ¼ 17 nM). This observation is in agreement with the results reported by Miyoshi et al., who found that the stereochemistry around the THF rings was of minor importance.16 Compared to the most potent acetogenin like bullatacin (IC50 0.8 nM), the activity is much weaker. One reason is that the spacer moiety between the THF ring and the c-lactone moiety (about 15 carbon atoms) is longer than the optimal length of the spacer (about 13 carbon atoms).17 Another reason is the length of the tail that links the THF ring. Compounds 1a and 1b possess 13 carbon atoms while bullatacin has 11 carbon atoms. As Miyoshi et al. reported,16 increase in hydrophobicity of the tail has a rather adverse effect on the activity due to some sort of trapping in the hydrophobic lipid bilayer of the mitochondria membrane. This would weaken the inhibition of mitochondrial complex I.
As shown in Scheme 3, c-lactone 19 was constructed as we had reported earlier starting from 18.6 Oxidation with mCPBA followed by thermal elimination afforded the c-lactone moiety 8. Both segments were coupled by the Sonogashira crosscoupling10 reaction. The most effective catalyst system in this reaction is 5 mol % of Cl2 Pd(PPh3 )2 , 10 mol % of CuI in Et3 N to furnish cross-coupled product 20 in 85% yield. Diimide reduction11 with p-TsNHNH2 and NaOAc in ethylene glycol diethyl ether under reflux afforded saturated product 21. When ethylene glycol dimethyl ether was used in this reaction, the reduction did not proceed smoothly. Finally, deprotection of MOM ethers with BF3 ÆEt2 O afforded candidate 1a.12 On the other hand, the other candidate 1b was synthesized from 7b using the same procedure as that employed for 1a (Scheme 4).
SPh
In conclusion, we have achieved total synthesis of two possible diastereomers of reticulatain-1 from building block 6. On the basis of the present data, it is difficult to
SPh I
Ref. 6 O 18
O
O 8
O
975
O 19
O
I
Scheme 3. Synthesis of the c-lactone part of 1a. Reagents: (a) mCPBA, toluene, reflux (78%).
a
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H. Makabe et al. / Tetrahedron Letters 45 (2004) 973–977 C12H25
O OMOM 7a
a
I
+ O
OMOM
O 8
C12H25
O O OMOM
OMOM
O 20 O
b
C12H25
O OMOM
O OMOM 21 O
c
C12H25
O
O OH
OH 1a
C12H25
O OMOM 7b
OMOM O
C12H25
O
O OH
OH
1b
Scheme 4. Synthesis of 1a. Reagents: (a) 5 mol % Cl2 Pd(PPh3 )2 , 10 mol % CuI, Et3 N (85%); (b) p-TsNHNH2 , NaOAc, ethylene glycol diethyl ether (61%); (c) BF3 ÆEt2 O, DMS (87%).
O C12H25 22
21
18
17
O
O
MTPA-(R)-O
O-(R)-MTPA (R)-MTPA-1a
C12H25 22
21
O
MTPA-(R)-O
O
18 17
O
O-(R)-MTPA (R)-MTPA-1b O
MTPA-(R)-O
O O-(R)-MTPA
pounds was examined with bovine heart mitochondrial complex I. Both compounds showed almost the same activity.
MTPA-(R)-O
22a
O-(R)-MTPA 22b
Figure 2. Bis-(R)-MTPA esters of 1a, 1b, and Fujimotos model compounds 22a and 22b.
Table 2. 1 H NMR chemical shifts of the bis-(R)-MTPA esters of 1a and 1b MTPA ester
17-H
18-H
21-H
22-H
(R)-MTPA-1a 22a (R)-MTPA-1b 22b
4.98 4.98 5.02 5.03
3.76 3.77 3.93 3.94
3.98 3.98 3.93 3.94
5.26 5.27 5.22 5.22
determine the absolute configuration of natural reticulatain-1. The 1 H NMR chemical shifts of bis-(R)-MTPA esters of 1a and 1b showed a clear difference. This indicates that if the bis-(R)-MTPA ester of natural 1 is available, the absolute configuration of reticulatain-1 will be determined. Inhibitory action of these com-
Acknowledgements This work was supported in part by a Grant-in-aid from the Japan Society for the Promotion of Science (15780084). We thank Ms. Keiko Hashimoto, Ms. Moemi Mizu, and Ms. Megumi Miyazawa of the Faculty of Agriculture, Shinshu University, for the 500 MHz NMR measurements. We also thank Prof. Dr. Mitsuru Hirota of the Faculty of Agriculture, Shinshu University, for obtaining Mass spectra.
References and notes 1. For recent reviews for Annonaceous acetogenins, see: (a) Alali, F. Q.; Liu, X.-X.; McLaughlin, J. L. J. Nat. Prod. 1999, 62, 504–540; (b) Zafra-Polo, M. C.; Figadere, B.; Gallardo, T.; Tormo, J. R.; Cortes, D. Phytochemistry 1998, 48, 1087–1117. 2. For recent total synthesis of mono-THF acetogenins, see: (a) Maezaki, N.; Kojima; Sakamoto, A.; Tominaga, H.; Iwata, C.; Tanaka, T.; Monden, M.; Damdinsuren, B.; Nakamori, S. Chem. Eur. J. 2003, 9, 389–399; (b) Cecil, A. R. L.; Brown, R. C. D. Org. Lett. 2002, 4, 3715–3718; (c) Makabe, H.; Hattori, Y.; Tanaka, A.; Oritani, T. Org. Lett. 2002, 4, 1083–1085; (d) Hu, T.-S.; Yu, Q.; Wu, Y.-L. J. Org. Chem. 2001, 66, 853–861; (e) Maezaki, N.; Kojima;
H. Makabe et al. / Tetrahedron Letters 45 (2004) 973–977
3. 4. 5. 6. 7. 8. 9. 10. 11. 12.
Sakamoto, A.; Tominaga, H.; Iwata, C.; Tanaka, T. Org. Lett. 2001, 3, 429–432. Tam, V. T.; Hieu, P. Q. C.; Chappe, B.; Robolt, F.; Figadere, B.; Cave, A. Bull. Soc. Chim. Fr. 1995, 132, 324–329. Saad, J. M.; Hui, Y. H.; Rupprecht, J. K.; Anderson, J. E.; Kozlowski, J. F.; Zhao, G. X.; Wood, K. V.; McLaughlin, J. L. Tetrahedron 1991, 47, 2751–2756. Sinha, S. C.; Keinan, E. J. Am. Chem. Soc. 1993, 115, 4891–4892. Makabe, H.; Tanaka, A.; Oritani, T. J. Chem. Soc., Perkin Trans. 1 1994, 1975–1981. Makabe, H.; Tanimoto, H.; Tanaka, A.; Oritani, T. Heterocycles 1996, 43, 2229–2248. Mitsunobu, O. Synthesis 1981, 1–28. Dodge, J. A.; Trujillo, J. I.; Presnell, M. J. Org. Chem. 1994, 59, 234–236. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 4467–4470. Marshall, J. A.; Piettre, A.; Paige, M. A.; Valeriote, F. J. Org. Chem. 2003, 68, 1780–1785. The data for 1a: mp 85–87 °C, ½a30 D +9.68° (c 1.00, CHCl3 ). IR (KBr) mmax cm1 : 3444, 3076, 2917, 2849, 1741, 1470, 1321, 1121, 1075, 1022, 950, 877, 718. 1 H NMR (CDCl3 , Me4 Si) d: 0.88 (3H, t, J ¼ 6:8 Hz), 1.20–2.00 (52H, m), 1.40 (3H, d, J ¼ 6:6 Hz), 2.00 (1H, br –OH), 2.26 (2H, t,
13. 14.
15. 16. 17.
977
J ¼ 7:5 Hz), 2.31 (1H, br –OH), 3.39 (1H, m), 3.80–3.90, (3H, m), 4.98 (1H, qd, J ¼ 6:6, 1.5 Hz), 6.98 (1H, d, J ¼ 1:5 Hz). 13 C NMR (CDCl3 , Me4 Si) d: 14.09, 19.22, 22.68, 25.19, 25.60, 25.97, 27.43, 28.61, 29.19, 29.31, 29.35, 29.52, 29.56, 29.61, 29.65, 29.67, 29.69, 29.73, 31.92, 32.63, 33.32, 71.65, 74.33, 77.36, 82.17, 83.22, 134.41, 148.77, 173.84. HREIMS (M)H2 O): Calcd for C37 H66 O4 574.4961, found 574.4930. The data for 1b: mp 87–90 °C, ½a28 D +2.34° (c 1.00, CHCl3 ). The IR, 1 H NMR, 13 C NMR, HREIMS data were identified with those of 1a. The discrepancy in the optical rotation value of the synthetic product with that reported for the natural product has been reported: (a) Sinha, S. C.; Sinha, S. C.; Keinan, E. J. Org. Chem. 1999, 64, 7067–7073; (b) Takahashi, S.; Kubota, A.; Nakata, T. Org. Lett. 2003, 5, 1353–1356. Shimada, H.; Nishioka, S.; Singh, S.; Sahai, M.; Fujimoto, Y. Tetrahedron Lett. 1994, 35, 3961–3964. Miyoshi, H.; Ohshima, M.; Shimada, H.; Akagi, T.; Iwamura, H.; McLaughlin, J. L. Biochim. Biophys. Acta 1998, 1365, 443–452. Takada, M.; Kuwabara, K.; Nakato, H.; Tanaka, A.; Iwamura, H.; Miyoshi, H. Biochim. Biophys. Acta 2000, 1460, 302–310.
Synthesis of two possible diastereomers of reticulatain-1 Hidefumi Makabe,a,* Aya Miyawaki,a Ryoko Takahashi,a Yasunao Hattori,a Hiroyuki Konno,b Masato Abec and Hideto Miyoshic a
Sciences of Functional Foods, Graduate School of Agriculture, Shinshu University, 8304 Minami-minowa, Kamiina, Nagano 399-4598, Japan b Department of Biological Science and Technology, Faculty of Engineering University of Tokushima, 2-1 Minamijosanjimacho, Tokushima 770-8506, Japan c Division of Applied Sciences, Graduate School of Agriculture, Kyoto University, Kita-shirakawa, Sakyo-ku, Kyoto 606-8502, Japan Received 25 September 2003; revised 20 November 2003; accepted 21 November 2003
Abstract—A convergent synthesis of two possible diastereomers of reticulatain-1 (1a and 1b) was accomplished. Comparison of the specific optical rotations of 1a and 1b did not allow for the strict determination of the absolute configuration. However, bis-(R)MTPA esters of 1a and 1b showed a clear difference in chemical shifts in the 1 H NMR spectra. If the bis-(R)-MTPA ester of natural reticulatain-1 (1) is available, the absolute configuration of 1 will be determined. Inhibitory action of these compounds was examined with bovine heart mitochondrial complex I. Both compounds showed almost the same activity. Ó 2003 Elsevier Ltd. All rights reserved.
Annonaceous acetogenins, that have been isolated from a number of tropical or subtropical plants of the Annonaceae, have attracted much attention due to a wide variety of biological activities, for example, cytotoxic, antitumoral, antimalarial, antibiotic, antiparasitic, and antifeedant. So far, more than 350 compounds have been isolated.1 Most of them possess one or more tetrahydrofuran (THF) rings, together with an a,b-unsaturated c-lactone part on a C-35 or C-37 carbon chain. Reticulatain-1 (1) is a mono-THF acetogenin,2 isolated from Annona reticulata in 1995.3 A similar compound corresponding to the well-known reticulatacin (2)4 was synthesized by Keinan5 and us.6 The absolute configuration of natural 1 has not been reported yet. However, because the erythro-trans-threo stereochemistry of the tetrahydrofuran ring of 1 has been determined by Figadere et al.,3 and the (S) configuration of the secondary methyl group of the c-lactone moiety is well known, it follows that the absolute stereochemistry of 1 is (17R,18R,21R,22S) or (17S,18S,21S,22R) (Fig. 1).
trans erythro C12H25
O
threo
O
O
OH
OH 21
18
O
22
reticulatain-1 (1)
OH
21 17
OH
18
O
22
OH
1a
17
OH 1b O
C12H25
O
O OH
OH
reticulatacin (2)
trans threo C12H25 OH
threo
OH
O O
O OH
(8'R)-corossoline (3)
Figure 1. The structure of reticulatain-1.
The two possible structures, 1a and 1b, would be very difficult to differentiate by 1 H NMR or 13 C NMR
Keywords: Annonaceous acetogenin; Antitumor; Mitochondrial complex I. * Corresponding author. Tel.: +81-265-77-1630; fax: +81-265-77-1700; e-mail: [email protected] 0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2003.11.109
spectroscopic data, because two stereogenic centers, that is, the THF ring part and the c-lactone moiety are separated by a long carbon chain. In a previous paper, we prepared chiral building block 4 for synthesizing (80 R)-corossoline (3), mono-THF acetogenins, which possess the threo-trans-threo stereochemistry of the
974
H. Makabe et al. / Tetrahedron Letters 45 (2004) 973–977 Ref. 7 +
CHO
C12H25
C12H25MgBr
OH
O
Ref. 7
Ref. 7 C12H25 C12H25
O
O OH
AD mix β
3 O OMOM 5
OMOM
O C12H25
4 Mitsunobu Inversion and Hydrolysis
C12H25
O
O OH
O 6
O OMOM 7a
OMOM
I
C12H25
O OMOM OMOM 7a trans erythro threo C12H25 O OH OH 1a
+
O
O
8 O O
Scheme 1. Synthetic strategy of reticulatain-1.
tetrahydrofuran ring. In this paper, we prepared another chiral building block 6 for synthesizing mono-THF acetogenins, which possess erythro-trans-threo stereochemistry by using the Mitsunobu inversion from 4 (Scheme 1). To utilize this methodology, we planned to synthesize two candidates of reticulatain-1 (1), 1a and 1b.
acrolein and laurylmagnesium bromide. Grignard reaction of acrolein with laurylmagnesium bromide gave allylic alcohol 9. Johnson–Claisen rearrangement with 1,1,1-triethoxyethane and a catalytic amount of propionic acid gave ester 10, which was then submitted to reduction with diisobutylaluminum hydride (DIBALH) to afford 11. The conversion of compound 11 to 4 was performed using the Sharpless epoxidation and dihydroxylation according to our previously published method.7
As shown in Scheme 2, the THF part 15 of 1a was constructed via a multi-step process starting from OH
a
CHO acrolein
C12H25
d
C12H25
OH
OH
O 6
C12H25
C12H25
O OMOM 14
h
OH OH
j O OMOM 16
C12H25
O
C12H25
O OMOM 15
O OMOM 13
OH
O
O
g
O
OTBS
i
OH
k O OMOM 17
O O-p-NBA O 12
O C12H25
f
O
O
4
C12H25
O
O OH
C12H25
c
10
9
11 e
CO2Et
C12H25
Ref. 7 C12H25
b
C12H25
O OMOM OMOM 7a
Scheme 2. Synthesis of tetrahydrofuran part of 1a. Reagents: (a) C12 H25 MgBr, Et2 O (95%); (b) CH3 C(OEt)3 , propionic acid (86%); (c) DIBALH, CH2 Cl2 (95%); (d) p-nitrobenzoic acid, DEAD, THF (85%); (e) NaOH, MeOH (91%); (f) MOMCl, i-Pr2 NEt, CH2 Cl2 (92%); (g) 60% AcOH, (96%); (h) TBSCl, Et3 N, DMAP, CH2 Cl2 (100%); (i) 1) MsCl, Et3 N, CH2 Cl2 2) TBAF, THF(96%); (j) lithium acetylide, ethylenediamine complex, DMSO (83%); (k) MOMCl, i-Pr2 NEt, CH2 Cl2 (94%).
H. Makabe et al. / Tetrahedron Letters 45 (2004) 973–977
The spectral data (1 H NMR, 13 C NMR, EIMS) of the synthetic 1a and 1b were in good agreement with those reported for natural 1.3 This indicates that the relative stereochemistry of natural 1 is erythro-trans-threo as reported by Figadere et al.3 The two synthetic samples (1a, 1b) could not be differentiated by the spectral data (1 H NMR, 13 C NMR, MS). On the other hand, their optical rotations showed different values. The specific rotation of synthetic 1a (½a30 D +9.68°, c 1.00, CHCl3 ) is lower than the reported value of natural occurring reticulatain )13 (½aD +22°, c 1, CHCl3 ). On the other 27 hand, that of 1b (½aD +2.34°, c 1.00, CHCl3 ) showed 13 a very small value. Judging from the specific optical rotations of 1a and 1b, it is difficult to determine the absolute configuration of natural reticulatain-1.2e;14 We also prepared the corresponding bis-(R)-MTPA esters from synthetic 1a and 1b. The chemical shifts of H-17, H-18, H-21, and H-22 of both 1a and 1b showed a clear difference and they were in good agreement with those of the methine protons of Fujimotos stereochemically defined model compounds (Fig. 2, Table 2).15
Table 1. Variation of the carboxylic acids in the Mitsunobu inversion of 4a
a
Acid
pKa
Yield (%)
Acetic acid Benzoic acid p-Nitrobenzoic acid
4.76 4.19 3.41
0 17 85
The reaction was carried out in THF at room temperature for 12 h.
Compound 4 was then subjected to the Mitsunobu reaction.8 In this reaction, the yields of products were highly dependent on the pKa values of acids perhaps due to the steric hindrance of the acetonide group.9 p-Nitrobezoate gave a good result. On the other hand, acetic acid or benzoic acid afforded the product in low yield (Table 1). Hydrolysis of p-nitrobezoate 12 with methanolic NaOH gave building block 6. The inverted secondary hydroxyl group of 12 was protected as the methoxymethyl (MOM) ether to afford 13. Selective deprotection of the acetonide group of 13 with 60% AcOH gave diol 14. Silylation of the primary hydroxyl group of 14 with t-butyldimethylchlorosilane (TBSCl), Et3 N, and 4-dimethylaminopyridine (DMAP) afforded 15. Successive treatment with methanesulfonyl chloride (MsCl), tetrabutylammonium fluoride (TBAF) furnished terminal epoxide 16. Alkynylation with lithium acetylide, an ethylene diamine complex, afforded alkyne 17. Protection of the secondary hydroxyl group gave the THF moiety 7a.
This indicates that if the bis-(R)-MTPA ester of natural 1 is available, the absolute configuration of reticulatain1 will be definitely established. Compounds 1a and 1b were tested as inhibitors of bovine-heart mitochondrial complex I. Both compounds exhibited almost the same activity (1a: IC50 ¼ 16 nM, 1b: IC50 ¼ 17 nM). This observation is in agreement with the results reported by Miyoshi et al., who found that the stereochemistry around the THF rings was of minor importance.16 Compared to the most potent acetogenin like bullatacin (IC50 0.8 nM), the activity is much weaker. One reason is that the spacer moiety between the THF ring and the c-lactone moiety (about 15 carbon atoms) is longer than the optimal length of the spacer (about 13 carbon atoms).17 Another reason is the length of the tail that links the THF ring. Compounds 1a and 1b possess 13 carbon atoms while bullatacin has 11 carbon atoms. As Miyoshi et al. reported,16 increase in hydrophobicity of the tail has a rather adverse effect on the activity due to some sort of trapping in the hydrophobic lipid bilayer of the mitochondria membrane. This would weaken the inhibition of mitochondrial complex I.
As shown in Scheme 3, c-lactone 19 was constructed as we had reported earlier starting from 18.6 Oxidation with mCPBA followed by thermal elimination afforded the c-lactone moiety 8. Both segments were coupled by the Sonogashira crosscoupling10 reaction. The most effective catalyst system in this reaction is 5 mol % of Cl2 Pd(PPh3 )2 , 10 mol % of CuI in Et3 N to furnish cross-coupled product 20 in 85% yield. Diimide reduction11 with p-TsNHNH2 and NaOAc in ethylene glycol diethyl ether under reflux afforded saturated product 21. When ethylene glycol dimethyl ether was used in this reaction, the reduction did not proceed smoothly. Finally, deprotection of MOM ethers with BF3 ÆEt2 O afforded candidate 1a.12 On the other hand, the other candidate 1b was synthesized from 7b using the same procedure as that employed for 1a (Scheme 4).
SPh
In conclusion, we have achieved total synthesis of two possible diastereomers of reticulatain-1 from building block 6. On the basis of the present data, it is difficult to
SPh I
Ref. 6 O 18
O
O 8
O
975
O 19
O
I
Scheme 3. Synthesis of the c-lactone part of 1a. Reagents: (a) mCPBA, toluene, reflux (78%).
a
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H. Makabe et al. / Tetrahedron Letters 45 (2004) 973–977 C12H25
O OMOM 7a
a
I
+ O
OMOM
O 8
C12H25
O O OMOM
OMOM
O 20 O
b
C12H25
O OMOM
O OMOM 21 O
c
C12H25
O
O OH
OH 1a
C12H25
O OMOM 7b
OMOM O
C12H25
O
O OH
OH
1b
Scheme 4. Synthesis of 1a. Reagents: (a) 5 mol % Cl2 Pd(PPh3 )2 , 10 mol % CuI, Et3 N (85%); (b) p-TsNHNH2 , NaOAc, ethylene glycol diethyl ether (61%); (c) BF3 ÆEt2 O, DMS (87%).
O C12H25 22
21
18
17
O
O
MTPA-(R)-O
O-(R)-MTPA (R)-MTPA-1a
C12H25 22
21
O
MTPA-(R)-O
O
18 17
O
O-(R)-MTPA (R)-MTPA-1b O
MTPA-(R)-O
O O-(R)-MTPA
pounds was examined with bovine heart mitochondrial complex I. Both compounds showed almost the same activity.
MTPA-(R)-O
22a
O-(R)-MTPA 22b
Figure 2. Bis-(R)-MTPA esters of 1a, 1b, and Fujimotos model compounds 22a and 22b.
Table 2. 1 H NMR chemical shifts of the bis-(R)-MTPA esters of 1a and 1b MTPA ester
17-H
18-H
21-H
22-H
(R)-MTPA-1a 22a (R)-MTPA-1b 22b
4.98 4.98 5.02 5.03
3.76 3.77 3.93 3.94
3.98 3.98 3.93 3.94
5.26 5.27 5.22 5.22
determine the absolute configuration of natural reticulatain-1. The 1 H NMR chemical shifts of bis-(R)-MTPA esters of 1a and 1b showed a clear difference. This indicates that if the bis-(R)-MTPA ester of natural 1 is available, the absolute configuration of reticulatain-1 will be determined. Inhibitory action of these com-
Acknowledgements This work was supported in part by a Grant-in-aid from the Japan Society for the Promotion of Science (15780084). We thank Ms. Keiko Hashimoto, Ms. Moemi Mizu, and Ms. Megumi Miyazawa of the Faculty of Agriculture, Shinshu University, for the 500 MHz NMR measurements. We also thank Prof. Dr. Mitsuru Hirota of the Faculty of Agriculture, Shinshu University, for obtaining Mass spectra.
References and notes 1. For recent reviews for Annonaceous acetogenins, see: (a) Alali, F. Q.; Liu, X.-X.; McLaughlin, J. L. J. Nat. Prod. 1999, 62, 504–540; (b) Zafra-Polo, M. C.; Figadere, B.; Gallardo, T.; Tormo, J. R.; Cortes, D. Phytochemistry 1998, 48, 1087–1117. 2. For recent total synthesis of mono-THF acetogenins, see: (a) Maezaki, N.; Kojima; Sakamoto, A.; Tominaga, H.; Iwata, C.; Tanaka, T.; Monden, M.; Damdinsuren, B.; Nakamori, S. Chem. Eur. J. 2003, 9, 389–399; (b) Cecil, A. R. L.; Brown, R. C. D. Org. Lett. 2002, 4, 3715–3718; (c) Makabe, H.; Hattori, Y.; Tanaka, A.; Oritani, T. Org. Lett. 2002, 4, 1083–1085; (d) Hu, T.-S.; Yu, Q.; Wu, Y.-L. J. Org. Chem. 2001, 66, 853–861; (e) Maezaki, N.; Kojima;
H. Makabe et al. / Tetrahedron Letters 45 (2004) 973–977
3. 4. 5. 6. 7. 8. 9. 10. 11. 12.
Sakamoto, A.; Tominaga, H.; Iwata, C.; Tanaka, T. Org. Lett. 2001, 3, 429–432. Tam, V. T.; Hieu, P. Q. C.; Chappe, B.; Robolt, F.; Figadere, B.; Cave, A. Bull. Soc. Chim. Fr. 1995, 132, 324–329. Saad, J. M.; Hui, Y. H.; Rupprecht, J. K.; Anderson, J. E.; Kozlowski, J. F.; Zhao, G. X.; Wood, K. V.; McLaughlin, J. L. Tetrahedron 1991, 47, 2751–2756. Sinha, S. C.; Keinan, E. J. Am. Chem. Soc. 1993, 115, 4891–4892. Makabe, H.; Tanaka, A.; Oritani, T. J. Chem. Soc., Perkin Trans. 1 1994, 1975–1981. Makabe, H.; Tanimoto, H.; Tanaka, A.; Oritani, T. Heterocycles 1996, 43, 2229–2248. Mitsunobu, O. Synthesis 1981, 1–28. Dodge, J. A.; Trujillo, J. I.; Presnell, M. J. Org. Chem. 1994, 59, 234–236. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 4467–4470. Marshall, J. A.; Piettre, A.; Paige, M. A.; Valeriote, F. J. Org. Chem. 2003, 68, 1780–1785. The data for 1a: mp 85–87 °C, ½a30 D +9.68° (c 1.00, CHCl3 ). IR (KBr) mmax cm1 : 3444, 3076, 2917, 2849, 1741, 1470, 1321, 1121, 1075, 1022, 950, 877, 718. 1 H NMR (CDCl3 , Me4 Si) d: 0.88 (3H, t, J ¼ 6:8 Hz), 1.20–2.00 (52H, m), 1.40 (3H, d, J ¼ 6:6 Hz), 2.00 (1H, br –OH), 2.26 (2H, t,
13. 14.
15. 16. 17.
977
J ¼ 7:5 Hz), 2.31 (1H, br –OH), 3.39 (1H, m), 3.80–3.90, (3H, m), 4.98 (1H, qd, J ¼ 6:6, 1.5 Hz), 6.98 (1H, d, J ¼ 1:5 Hz). 13 C NMR (CDCl3 , Me4 Si) d: 14.09, 19.22, 22.68, 25.19, 25.60, 25.97, 27.43, 28.61, 29.19, 29.31, 29.35, 29.52, 29.56, 29.61, 29.65, 29.67, 29.69, 29.73, 31.92, 32.63, 33.32, 71.65, 74.33, 77.36, 82.17, 83.22, 134.41, 148.77, 173.84. HREIMS (M)H2 O): Calcd for C37 H66 O4 574.4961, found 574.4930. The data for 1b: mp 87–90 °C, ½a28 D +2.34° (c 1.00, CHCl3 ). The IR, 1 H NMR, 13 C NMR, HREIMS data were identified with those of 1a. The discrepancy in the optical rotation value of the synthetic product with that reported for the natural product has been reported: (a) Sinha, S. C.; Sinha, S. C.; Keinan, E. J. Org. Chem. 1999, 64, 7067–7073; (b) Takahashi, S.; Kubota, A.; Nakata, T. Org. Lett. 2003, 5, 1353–1356. Shimada, H.; Nishioka, S.; Singh, S.; Sahai, M.; Fujimoto, Y. Tetrahedron Lett. 1994, 35, 3961–3964. Miyoshi, H.; Ohshima, M.; Shimada, H.; Akagi, T.; Iwamura, H.; McLaughlin, J. L. Biochim. Biophys. Acta 1998, 1365, 443–452. Takada, M.; Kuwabara, K.; Nakato, H.; Tanaka, A.; Iwamura, H.; Miyoshi, H. Biochim. Biophys. Acta 2000, 1460, 302–310.